Centre de recherche en cancérologie - Lyon

INCa (Institut National du Cancer)
DGOS (Direction Général de l’Offre de Soins)
ANR (Agence Nationale de la Recherche)
Ligue Nationale contre le Cancer
Fondation ARC pour la recherche sur le cancer
Fondation Bristol Myers Squibb
Fondation pour le Recherche Médicale
Fondation de France
Fondation Synergie Lyon Cancer
Région Auvergne Rhône-Alpes (AURA)
Métropole de Lyon
Cancéropôle CLARA
Novartis, Astra-Zeneca, Roche, Genentech

SCIENTIFIC COLLABORATIONS

Local at Cancer Research Center of Lyon
-Team Alain Puisieux
-Team Jean-Jacques Diaz
-Team Christophe Caux
-Team Peter Mulligan

National
-Team Vassili Soumelis, Institut Curie -> Hôpital St Louis
-Team Salem Chouaib, Institut Gustave Roussy
-Team Marie-Caroline Dieu-Nosjean, Pitié-Salpétrière
-Inclusion centers for LIBIL (NCT02511288; https://clinicaltrials.gov/ct2/show/NCT02511288)
and LIBELULE (NCT03721120; https://clinicaltrials.gov/ct2/show/NCT03721120) programs
-Inclusion centers for the IHNPACT (NCT01524978) program
-Integrated Cancer Research Sites partnering in the OSIRIS program (https://en.e-cancer.fr/OSIRIS-a-national-data-sharing-project)

International
-World Innovative Network in personalized cancer medicine (WIN)
-Scott M. Lippman, UCSD Moore Cancer Center, San Diego, CA
-Mark Lingen, University of Chicago, IL
-Senada Koljenovic, Erasmus MC, Netherlands
-Paolo Bossi, Brescia, Italy
-Moshe Elkabets, Ben Gurion University, Israel
-Charbel Darido, Peter Mac Callum Cancer Center, Melbourne, Australia
-Christine M Lovly, University of Vanderbilt, USA
-Roman Thomas, Cologne, Germany

Biotechs
-Inivata (liquid biopsies, amplicon-based panels) : https://www.inivata.com/
-HTG Molecular Diagnostics, Inc. (gene expression panels for FFPE samples): https://www.htgmolecular.com/
-HITACHI Healthcare (Biomarkers of response to proton beam therapy): http://www.hitachi.com/businesses/healthcare/
-Cellenion R & D program for the implementation of single cell analysis as a biomarker in oncology: https://www.cellenion.com/

OBJECTIVES

Our goal is to understand the longitudinal dynamics of head and neck cancer to intercept transformation of premalignant lesions, prevent the development of second primary tumors and improve treatment efficacy. Our strategy is to integrate clinical, pathological and molecular profiles to unravel the dynamic changes during early stages of tumorigenesis and under the selective pressure of systemic and radiation therapies. Our specific aims are as follow: to determine the evolutionary dynamics during the early stages of tumorigenesis, mainly in the oral cavity; to unravel the diversity and heterogeneity of head and neck cancer and their relevance for improved patient stratification; and to identify new candidate targets for patients with squamous cell carcinoma.

PROJECTS

Our team is focusing on head and neck (HN) disease from preneoplasia to established squamous cell carcinoma (SCC), before and after systemic therapy. Our ultimate goal is to reduce the incidence of SCCHN by intercepting transformation of oral premalignant lesions or by preventing the development of second primary tumors (SPTs), and by improving the treatment efficacy of established tumors. Our scientific objective is to understand the longitudinal dynamics of SCCHN to develop clinically relevant preventive and treatment strategies at specific time points of the natural history. We integrate clinical, pathological and molecular profiles both in human samples and preclinical models to unravel the dynamic changes during early stages of tumorigenesis and under the selective pressure of therapy, to reveal vulnerabilities that may in turn translate into new treatment and prevention strategies.

Aim 1 is to understand the genetic evolutionary trajectories underlying premalignant lesions progression, the co-evolution between premalignant lesions and the immune micro-environment and to integrate phenotypic (expression profiles), genetic and immune profiling to improve risk assessment and to develop the rational for innovative interception and preventive strategies.

Aim 2 is to evaluate the diversity and heterogeneity of SCCHN before treatment initiation and at the time of progressive disease to refine the current molecular classification of SCCHN, and test its relevance for improved patient stratification.

Aim 3 is to identify new targets through a systematic and comprehensive identification and validation of non-canonical membranous (externalized) proteins in SCCHN, using an in silico and a proteomic approach.

Our work is translational and multidisciplinary, combining the expertise of basic and translational scientists and physicians. We are strongly involved in the training of biologists, physicians and pharmacists. The team is actively collaborating with number of teams at CRCL, nationally and internationally. We have developed expertise in analyzing, integrating high-throughput and clinical data, and data mining of publicly available genomic data, which is often the basis of productive collaborations with other teams. Our work also involves socio-economic interactions through collaborations with pharma companies (ancillary studies) and biotechs. Specifically, we study longitudinal liquid biopsies for the study of the dynamics of cancer (Inivata, Illumina…) and the transcriptomic analysis of formalin-fixed paraffin embedded tissue (HTG Molecular Diagnostics). Another example is the ongoing funded effort with Cellenion to develop new approaches for single cell analysis.

MAIN PUBLICATIONS

1. Rodon J., …, Saintigny P., …, Kurzrock R. Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial. Nat Med. 2019 May;25(5):751-758.

2. Foy JP., Bertolus C., Ortiz-Cuaran S., Albaret MA., …, Destandau S., Souza G., …, Saintigny P. Immunological and classical subtypes of oral premalignant lesions. Oncoimmunology. 2018 Sep 21;7(12):e1496880.

3. Albaret MA., …, Paré A., …, Saintigny P., Diaz JJ. Externalized Keratin 8: A Target at the Interface of Microenvironment and Intracellular Signaling in Colorectal Cancer Cells. Cancers (Basel). 2018 Nov 16;10(11). pii: E452.

4. Saintigny P., Mitani Y., Pytynia KB., Ferrarotto R., Roberts DB., Weber RS., Kies MS., Maity SN., Lin SH., El-Naggar AK. Frequent PTEN loss and differential HER2/PI3K signaling pathway alterations in salivary duct carcinoma: Implications for targeted therapy. Cancer. 2018 Sep 15;124(18):3693-3705.

5. Saintigny P., William WN Jr., Foy JP., Papadimitrakopoulou V., Lang W., Zhang L., Fan YH., Feng L., Kim ES., El-Naggar AK., Lee JJ., Mao L., Hong WK., Lingen MW., Lippman SM. Met Receptor Tyrosine Kinase and Chemoprevention of Oral Cancer. J Natl Cancer Inst. 2018 Mar 1;110(3).

6. Martinez P., Mallo D., Paulson TG., Li X., Sanchez CA., Reid BJ., Graham TA., Kuhner MK., Maley CC. Evolution of Barrett’s esophagus through space and time at single-crypt and whole-biopsy levels. Nat Commun. 2018;9(1):794.

7. Foy JP., Bazire L., Ortiz-Cuaran S., Deneuve S., Kielbassa J., Thomas E., Viari A., Puisieux A., Goudot P., Bertolus C., Foray N., Kirova Y., Verrelle P., Saintigny P. A13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes. BMC Med. 2017 Sep 1;15(1):165.

8. Foy JP., Bertolus C., …, Albaret MA., Ortiz-Cuaran S., …, Fayette J., …, Zrounba P., …, Saintigny P. The immune microenvironment of HPV-negative oral squamous cell carcinoma from never-smokers and never-drinkers patients suggests higher clinical benefit of IDO1 and PD1/PD-L1 blockade. Ann Oncol. 2017 Aug 1;28(8):1934-1941.

9. Morel AP …, Saintigny P …, Puisieux A. A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability. Nat Med. 2017 May;23(5):568-578.

10. Ferrari A., …, Saintigny P., Birnbaum D., Viari A., Thomas G. A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers. Nat Commun. 2016 Jul 13;7:12222.

11. Timmer MR*., Martinez P.,*…., Derivation of genetic biomarkers for cancer risk stratification in Barrett's Oesophagus: a prospective cohort study. Gut, 2016 Oct;65(10):1602-10.

12. Ortiz-Cuaran S*., …., Heterogeneous Mechanisms of Primary and Acquired Resistance to Third-Generation EGFR Inhibitors. Clin Cancer Res. 2016 Oct 1;22(19):4837-4847.

13. Martinez P., ..., Dynamic clonal equilibrium and predetermined cancer risk in Barrett’s oesophagus. Nat Commun. 2016;7:12158.

14. Lavery DL., Martinez P., Gay LJ., Cereser B., Novelli MR., Rodriguez-Justo M., ... Jansen M. Evolution of oesophageal adenocarcinoma from metaplastic columnar epithelium without goblet cells in Barrett's oesophagus. Gut, 2016;65(6):907-913.

15. Lavergne V., Harliwong I., Jones A., Miller D., Taft RJ., Alewood PF. Optimized deep-targeted proteotranscriptomic profiling reveals unexplored Conus toxin diversity and novel cysteine frameworks. Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):E3782-91.

16. Lovly CM., …, Ortiz-Cuaran S., …., Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer. Nat Med. 2014 Sep;20(9):1027-34.

17. Fernandez-Cuesta L*., Plenker D*., …, Ortiz-Cuaran S., …., CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discov. 2014 Apr;4(4):415-22.

18. Gerlinger M., Horswell S., Larkin J., Rowan AJ., Salm MP., …Martinez P., …, Swanton C. Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nature Genetics, 2014;46(3):225-233.

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UMR INSERM 1052 CNRS 5286 - CENTRE LEON BERARD
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